HU227919B1 - Novel amlodipine camsylate and method for preparing thereof - Google Patents

Description

Amlodipine of Formula (2) - Chemical Name S-Ethyl-S-phenyl-S-S-S-aminoethoxymethyl) - (4-chlorophenyl) -6-methyl-1,4-dihydro-3,5-pyridine -dicarboxylate - a long-acting calcium channel blocker that is used to treat cardiovascular diseases such as angina, hypertension and haemopoietic heart failure.

EP 89167 discloses various types of pharmaceutically acceptable amlodipine salts. Pharmaceutically acceptable salts are prepared by the addition of a pharmaceutically acceptable acid to form an acidic, non-toxic salt of amlodipine, e.g. hydrochloride, hydrobromide, sulfate, phosphate or hydrogen phosphate, steel, maize, veneer, lactal, tartrate, citrate and gluconate. Of these salts, maize is most preferred.

Amlodipine can also be used as a free base for medical purposes. However, since amorphous amlodipine exhibits low stability, it is preferable to use it as a pharmaceutically acceptable acid addition salt thereof.

KR 95-8710 proposes that a pharmaceutically acceptable salt should meet four physico-chemical requirements: high solubility, good stability, non-hygroscopic, and use for tabletting purposes.

Most amlodipine salts are amorphous and are difficult to prepare in pure form. An amlodipine acid addition salt that meets all of the above requirements has yet to be developed. For example, even in the case of amladipine maleate, which is suggested as the most preferred pharmaceutical form of amlodipine, it has been found that although its water solubility is relatively high, it is degraded in solution within a few weeks. .. » ^f ' _x & t .... y lA JJ12

KR SS-7228 discloses that amlodipine benzenesulfonate (hereinafter "amlodipine besylate") has high solubility and good stability and is suitable for the preparation of a pharmaceutical composition. However, amlodipine besylate is a derivative of toxic benzenesulfonic acid, which raises the issue of safety.

♦ »*«

The inventors of the broadsheet sought to develop a new, crystalline -amlodiple that fulfills all the necessary properties

Accordingly, it is a primary object of the present invention to provide a novel crystalline amlodipine salt having low toxicity and pharmacologically acceptable properties.

In one aspect, the invention provides a process for the preparation of crystalline amlool spin using camphorsulfonic acid which has a lower toxicity compared to benzenesulfonic acid.

In another aspect, the invention provides amlodipine camsylate of formula (I), which is prepared by the process of the invention.

In another aspect, the invention provides a pharmaceutical composition for the treatment of cardiovascular disease comprising amlodipine camsylate as an active ingredient,

Brief description of the drawings

The above and other objects and features of the invention will be apparent from the following description and the accompanying drawings, which are as follows:

Figure 1: X-ray diffraction study of the amlodipine camsylate of the invention;

Figure 2: X-ray diffraction examination of amlodipine besylate:

Figure 3A shows the adhesion of amlodipine camsylate and amiodipine besylate according to the invention

The present invention relates to a process for the preparation of a crystalline amlodipine salt using low-toxicity camphorsulfonic acid.

More specifically, the process of the invention comprises the following steps:

(a) Dissolve the amlodipine of formula (2) in an organic solvent:

♦ *

b) adding an organic solvent solution of camphorsulfonic acid to the solution containing amlodipine and stirring the mixture for the time necessary to form a solid;

e) filtering, washing and drying the solid.

The crystalline amlodipine salt of the present invention can be prepared by adding an acid to the amlodipine solution or by adding the acid to the reaction elution for the preparation of amlodipine.

In step (a), amlodipine is preferably used in a concentration of 3 to 60% by weight, more preferably 10 to 30% by weight, to effectively accelerate crystallization.

The camphorsulfonic acid used in step b) may include, but is not limited to, a

(1S) - (+ ') - W-camphorsulfonic acid of formula (3), a

The (1R) - (-) - 10-camphorsulfonic acid of formula _z - _sg , h (4) and the racemic 10-camphorsulfonic acid The camphorsulfonic acid is preferably 0.1 to 5.0 equivalents based on the amount of amlodipine, more preferably 1.0 to 1 equivalent. , 3 equals kφφ

It is used in an amount of less than X.

The organic solvent used in step (a) or (b) includes methanol, ephanol, isopropanol, and acetonitrile,

In step b), the solid is preferably formed at a temperature of -10 ° C to 50 ° C, preferably G ° C to 25 ° C.

The present invention further provides an amlodipine visual acuator produced by the process of the invention having low toxicity and pharmacologically acceptable properties.

X-ray diffraction confirms that the crystalline form of the crystalline amlodipine salt of the invention, the amlodipine crystalline form, is different from the crystalline form of the amorphous compound or amlodipine besylate (Id. Figs. 1 and 2). and based on NMR analysis its chemical structure corresponds to formula (1).

It is well known that amiodipln-bezilate is the most suitable pharmaceutical formulation but exhibits stability problems due to its use of toxic benzenesulfonic acid. The present invention overcomes this problem by employing camphorsulfonic acid which is of low toxicity compared to benzenesulfonic acid.

The toxicity of camphorsulfonic acid and benzenesulfonic acid was compared according to the Registry of Toxic Effects of Chemical Substances (RTECSj) and. Comparative results are shown in Table 1.

♦ ♦

Table 1

Material Application way The investigator animal Dose Reference Benzene- sulfonic acid Orally Rat LDso 890 μΙ / kg A1HAAP 23,95,1962 skin .Cat L0so1ög / kg JPETAB 84,358,1945 Orally Vadmada- Cancer LOsö75mg / kg TXAPA9 21,315,1972 (tSHAMÖ- camphor- szuilönsav Under Boron Mouse LD50 2502 mg / kg Phare 1,150,1946 (±) -1O-camphor sulfonic acid Orally Quail .................................... LD 50> 318 mg / kg EESAOV 8,149,1982

• # LD50- 50 '% lethal dose, LDto- the minimum lethal dose mt is shown in Table 1 as it is impossible to compare LD 50 values between species, making direct comparison of camphorsulfonic acid and benzenesulfonic acid toxicity difficult, but it can be confirmed that The camphorsulfonic acid used in the present invention exhibits less toxicity than benzenesulfonic acid

The invention further provides a pharmaceutical composition for the treatment of cardiovascular diseases comprising as active ingredient the amiodipine camsylate of the invention together with pharmaceutically acceptable excipients, carriers or diluents.

The pharmaceutical compositions may be prepared by any of the conventional methods. Preferably, the active ingredient is mixed in the preparation of the composition

or may be diluted with a carrier, or contained in a carrier, which may be a capsule, sachet or other carrier. If the carrier serves as a diluent, it may be a solid, semi-solid, or liquid carrier for excipient, excipient or medium. . Thus, the compositions may be in the form of tablets, pills, powders, sachets, canes, suspensions, emulsions, solutions, syrups, aerosols, soft and hard gelatin capsules, sterile injectable solutions, sterile packaged powders, and the like. shape.

Suitable carriers, binders and diluents include lactose, dextrose, sucrose, serbitol, mannil, starches, acacia, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinyl cellulose, polyvinyl cellulose, benzoates, propyl hydroxybenzoates, talc, magnesium stearate and mineral oils. In addition, the compositions may also include fillers, anti-caking agents, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives, and the like. The compositions of the present invention may be formulated so as to release rapidly, sustainably or delayedly after administration of the active ingredient to the mammal in any manner known in the art.

The pharmaceutical compositions of the present invention may be administered by a variety of routes including oral, iris, subcutaneous, intravenous and intramuscular. When administered to humans, the typical daily dose of amiodipine carmylis is approximately 1 mg / kg. 1.0 to 10.0 mg / kg body weight, preferably 5.0 to 8.0 mg / kg body weight, and may be administered in a single dose or in divided doses.

However, it will be appreciated that the actual amount of active ingredient administered may be determined by taking into consideration various relevant factors, including the condition to be treated, the route of administration selected, the age, sex and weight of the patient and the severity of the patient's symptoms. it is not intended to limit the scope of the invention in any way.

The following examples and ghosts are intended only to illustrate the invention and are not intended to limit its scope,

Example 1

Camsylate amlodipine. Production I,

12.25 g (0.03 mol) of amlodipine (Hanml Pharm, Co. Ltd.) were dissolved in 50 ml of methanol, cooled to 10 ° C and then (1S) -1O-camphorsulfonic acid (7.8 g, 0.336 mole) was added gradually. (Aldnch) in methanol (19.5 ml). The reaction mixture was stirred at room temperature for 2 hours, then the resulting solid was filtered, washed with methanol (25 mL) and dried. This gave 18.7 g (86.8%) of the title compound as white crystals.

M.p. 198 * 0-202 ° C.

(300Hz, DMS0-d _s) (ppm): 8.42 (s, 1H); 7.82 (br, 3H); 7.35-7.13 (m, 4H, ArH); 5.30 (s, 1H); 4.73-4.55 (d, d, 2H): 3.98 (g, 2H); 3.85 (m, 2H): 3.50 (s, 3H); 3.34 (s, 2H); 3.08 (m, 2H); 2.90-2.35 (dd, 2H); 2.70 (m, 1H); 2.31 (s, 3H);

2.28-2.21 (m, 1H): 1.95-1.77 (m, 3H): 1.27 (m, 2H); 1.28 (t, 3H): 1.05 (s, 3H); 0.74 (s,

Example 2

Preparation of Amcdipine Camellia II,

Amlodipine (12.25 g, 0.03 mol) was dissolved in methanol (50 ml), cooled to 10 ° C, and then 7.8 g (0.336 mol) of (1R) -10-camphorsulfonic acid (Aldnch) was prepared in 19.5 ml of methanol. of the solvent to give 15.4 g (80.0% yield) of the title compound as white crystals, m.p.

¢.

> * «Λ *» * «

· Using the procedure of Example *.

M.p .: 198 ^° C-2O4 ° C.

¹ H-NMR (300Hz, DMSO-d 6) δ (ppm); 8.42 (s, 1H); 7.82 (br, 3H); 7.35-7.13 (m, 4H, ArH); 5.30 (s, 1H): 4.73-4.55 (d, d, 2H): 3, 96 (g, 2H); 3.65 (m, 2H); 3.50 (s, 3H); 3.34 (s, 2H); 3.08 (m, 2H); 2.90-2.35 (dd) , 2H); 2.70 (m, 1H); 2.31 (s, 3H);

2.28-2.21 (m, 1H); 1.95-1.77 (m, 3H); 1.27 (m, 2H); 1.26 (1H, 3H); 1.05 ($, 3H); 0, '4 (s,

Example 3

Preparation of Amlodipine-Camsylate

12.25 g (0.03 mol) of amlodipine was dissolved in 50 ml of methanol, 10 ° C ^ö iehőtöttük then gradually added 7.8 g (0.338 moh (±) -10-camphor ^sulfonic: acid (Aldhdh) 19.5 A solution of methanol in methanol (16 ml, 83.2%) was obtained as white crystals using the procedure of Example 1.

M.p .: 198 ^Q C 204 ° C ¹ H NMR (300Hz, DMSO-ds) (ppm); 8.42 (s, 1H); 7.82 (br, 3H); 4H, ArH); 5.30 (s, 1H); 4.73-4.55 (d, d, 2H); 3.98 (g, 2H); 3.85 (m 3 H); 3.34 (s, 2H); 3.03 (m, 2H); 2.90-2.35 (dd, 2H); 2.70 (m, 1H)

2.28-2.21 (m, 1H); 1.95-1.77 (m, 3H); 1.27 (m, 2H); 1.28 (t, 3H): 0.74 (s, 3H)

7.35-7.13 (m,

2 H); 3.50 (s, 2.31 (s, 3H); 1.05 (s, 3H);

Experimental Example 1 Solubility test

The solubility of an amlodipine salt in water is preferably greater than 1 mg / ml at a pH of 1 to 7.5, preferably at a pH of 7.4 in the blood. Accordingly, the solubility and saturation pH of the amlodipin <RTI ID = 0.0> 1-camnates </RTI> prepared in Examples 1 and 2 were measured and compared with the values of amlodipine besylate (KE 95-7228). The measurement was performed as described in the Korean Pharmacopoeia (Korean Pbarmacopoeia: Korean Principle of Health and Welfare, General Principle of Medical Supplement, Volume 1, Article 29; 7 Revised Editions), which comprises the steps of dissolving each compound in distilled water. water to obtain a saturated solution, then the saturated solutions are analyzed by liquid chromatography, and the. based on the amount of amlodipine, the amount of compound dissolved is determined.

Table 2

Salt | Solubility (mg / ml) j ΐ Saturation pH Amlodipine besylate | 1398 I 8.2 Amlodipine Camsilate (S) Example 1 ΐ 1.225 ................................................. i | 8.0 Example 2 amlodipine chemil (R) | 1,250 | 8.2

Table 2 shows that the saturation pH of the amiodipine camsylate of the present invention is similar. amlodipine besylate, but slightly lower in solubility than amlodipine besylate, probably due to the difference in molecular weight between amlodipine besylate (molecular weight ~ 641.18) and amitrippin besylate (molecular weight ~ 589.08).

Ghost Example 2 Stability Test

The time-dependent stability of the amiodipine camzylate of the invention prepared in Examples 1 and 2 was measured and compared to the amlodipine besylate stearate.

* · · <* ^Χ · xs *** * ·. ~. ^{ν s} . More particularly, each of compounds 55 ®C-one _and approx. It was stored at 50% relative humidity and after 1, 2, 3 and 4 weeks the remaining amount of active amlodipine was determined by liquid chromatography.

Table I

As shown in Table 3, while the amiodlpin besifate underwent a small but significant degradation after the first week, the amiodipine camsylate of the invention remained stable over the four-week period. Consequently, the amiodipine camsylate of the invention is more stable than the amiodipine hesylate.

Experimental Example 3

Absorption test

If a solid formulation of a drug is to be prepared, it is important that the active ingredient is not absorbent. Therefore, the lime content of the amiodipine camsylate of the present invention was measured and compared with amlodipine besylate.

All compounds were exposed to the following two environments; At 37 ° C with% RH for 24 hours (environment 1) and at 30 ° C with 95% <♦ «Α« «« »V for 3 days (environment 2), this was determined as follows. the moisture content of the compounds is described in KR 1895-7228.

spreadsheet

- Salt Initial moisture content (%) 1 environment P) 2. environment (%) Amlodipine besylate 0.05 0.05 0.15 Example 1 amlodipln-kamzi sees (S) 0.05 0.05 0.15 Example 2 am 1 odi pl n-chamber 1 over (R) 9.05 0.05 0.15

The data in Table 4 show that neither is the amiodipine cell according to the invention. neither amlodipine wool is absorbent, i.e., non-hygroscopic.

Experimental Example 4

Comparative adhesion test

The adhesion property of the amiodigin camsylate of the invention was determined and compared to the adhesion property of amiodipine besylate as follows,

Each active ingredient was tabletted as described in KR 95-7228 and the lump of adherent material adhering to the tablet machine stamp was dissolved in methanol at various tableted volumes and quantified by spectrometer.

The mean value for multiple measurements was determined from the slope of the linear lines shown in Figure 3.

Table 5

Absorbed tablet volume (pg) Amlodipine besylate Amlodipine camsylate Camsylate / besilate tablet Weight AVG. S.D. AVG. S.D. AVG. S.D. 50 32.9 5.6 33.0 8.2 1.00 0.08 100 60.6 2.5 60.6 9.1 0.99 0.11 150 102.7 15.7 101.1 ........................ 14.6 0.99 0.01 220 183.8 1.1 177.1 2.1 0.96 0.01 250 235.1 5.3 234.8 13.3 1.00 0.03 300 242.7 2.6 235.4 1.4 0.97 0.02

Table 5 shows that the amiodinyl camsylate of the invention and the amiodinyl betilate according to the invention have the same anti-adhesive properties (see Fig. 3).

Although the invention has been described in the above specific embodiments, it will be understood that ...........

art that the present invention can prepare different mődosífásaif digs variants, which are also included within the scope of the invention ^Λ defined by the scope of claims.

Claims (8)

Claims Claims 1. An amiodipine-camsylate of formula (1) H OOjCHjCHj · kaaf in ful acid 2, A process for the preparation of amlodipine camellia according to claim 1, characterized in that b) adding an organic solvent solution of camphorsulfonic acid to the solution containing amphodipine and stirring the mixture for a period sufficient to form a solid; c) filtering, washing and drying the solid. 3. A process according to claim 2 wherein the (1S) - {- R-10? - camphorsulfonic acid of formula (3) and (1-RH -) <. A compound selected from 10-camphorsulfonic acid and racemic W-camphorsulfonic acid is used. κο, δ · 'κ a rS SO,. H p) The process according to claim 2, wherein the mixture used in reaction step b) has an amiodlpine concentration of from 3 to 60% by weight. 5. The process of claim 2, wherein the amount of carnforsulfonic acid is from 0.1 to 5.0 equivalents relative to the amount of amlodipine. 6. A process according to claim 2, wherein the organic solvent used in a) or b) is selected from the group consisting of methanol, ethanol, isopropanol and acetonin. The process according to claim 2, wherein the solid is formed at a temperature of -10 ° C to 50 ° C. A pharmaceutical composition for the treatment of cardiovascular diseases, comprising as active ingredient the amlodipine camphor blocking agent according to claim 1. The Plenipotentiary;